Continuing the paradigm shift in the treatment of idiopathic membranous nephropathy

I read with interest the recent Review by P. Ruggenenti et al. (Treatment of membranous nephropathy: time for a paradigm shift. Nat. Rev. Nephrol. 13, 563–579; 2017)¹. The observed inconsistency in therapeutic responses with conventional therapies directed at T cells and B cells², as well as the superior complete remission rates (53%) achieved with rituximab in patients with recurrent membranous nephropathy post-transplantation³ compared to rates in those with native kidneys (13.6–19%)^4,5, highlight the important role of T cells in autoimmune kidney diseases⁶ and the likely added value of T cell-targeted therapies in addition to anti-CD20 monoclonal antibody therapy in increasing remission rates. These observations imply the existence of different immunopathogenic signatures — primarily B cell-mediated pathways with a component of T cell help^6,7 — in addition to distinct mechanisms of autoantibody and alloantibody secretion by different B cell lineages, for example, by CD20⁺ activated B cells in spleen and lymph nodes, CD19⁺CD20⁻ plasmablasts and short-lived plasma cells in blood, and CD19⁻CD20⁻CD38⁺CD138⁺ long-lived memory plasma cells located in the bone marrow and ectopically in the inflamed kidney⁸. These non-proliferating long-lived memory plasma cells produce considerable amounts of IgG autoantibodies and alloantibodies, and provide the basis for humoral memory and refractory autoimmune diseases^7,8,9,10.

As pointed out by Ruggenenti et al., the lack of CD19 and CD20 expression by long-lived memory plasma cells renders these cells resistant to depletion by anti-CD20 monoclonal antibodies^1,5,9. This resistance might explain the limited rate of sustained complete remission and recovery achieved by rituximab in patients with idiopathic membranous nephropathy, despite successful depletion of circulating B cells^4,5,10,11,12. I agree that use of plasma-cell-depleting therapies, such as the newly introduced anti-CD38 monoclonal antibodies and the less specific proteasome inhibitors with anti-B cell and anti-T cell activities¹³, might offer novel therapeutic alternatives for patients with idiopathic membranous nephropathy, at least in those who are refractory or only partially respond to combined conservative treatment plus rituximab therapy¹². Whether new second and third generation anti-CD20 monoclonal antibodies can achieve higher rates of sustained complete remission than rituximab¹ remains to be determined, but such agents do not target long-lived memory plasma cells^8,14. Surprisingly, another anti-CD20 monoclonal antibody, ofatumumab, failed to demonstrate superiority over rituximab as salvage chemotherapy in patients with relapsed or refractory diffuse large B cell lymphoma¹⁵. New immunologic biomarkers are needed to help to identify patients who are likely to respond to T cell³, B cell^7,8, or combination therapy^12,14. In addition to measuring CD19 and CD20 (Refs 1,4,5,9,11), assessment of patients with membranous nephropathy should include measurement of the long-lived memory plasma cell markers, CD38 and CD138, particularly in patients with relapsing or rituximab-resistant disease^{7,8,9,10,12,14}.